Proposal Summary: To assure adequate energy resources for the energetically demanding process of reproduction, central reproductive physiology is influenced by hormonal and neural signals of energy balance. As a result, maladaptive changes in energy homeostasis in either the positive or negative direction can exert dramatic effects on reproductive success and fertility. For example, both anorexia nervosa and obesity are associated with an increased likelihood for reproductive disorders or infertility. Despite the importance of physiological interactions between metabolic state and reproduction, the underlying mechanisms and neural pathways linking metabolism and reproduction are not fully understood. One key pathway connecting metabolism and reproduction is the central melanocortin system. Previous studies have determined that alpha melanocyte stimulating hormone (?-MSH), agouti related protein (AgRP), and melanocortin 4 receptor (MC4R) modulate multiple aspects of reproductive function. Here, we provide data demonstrating that the melanocortin-3 receptor (MC3R) plays critical, bidirectional roles in integration of energy and reproductive states. We show defects in the hypothalamic-pituitary-gonadal axis, as well as defects in energy homeostasis in response to reproductive state in MC3R KO mice. Therefore, the current proposal will characterize the anatomical, physiological, and behavioral role of the MC3R in reproductive function. We will first map the anatomical distribution of the MC3R within hypothalamic reproductive circuitry. Subsequent electrophysiological assays will be performed to determine how the MC3R modulates the cellular physiology of the central reproductive neural circuitry located in the hypothalamus. Finally, we will utilize a combination of genetic, pharmacological, and DREADD (designer receptors exclusively activated by designer drugs) assays to determine the contribution of the MC3R to hypothalamic-pituitary-gonadal axis function and reproductive physiology. Overall, this proposal will provide a holistic view of the behavioral, physiological, and mechanistic functions of the MC3R in mediating interactions between reproductive function and energy homeostasis, potentially providing novel therapeutic strategies for infertility in the increasing obese and anorexic populations.